التفاصيل البيبلوغرافية
| العنوان: |
Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling. |
| المؤلفون: |
Baumgärtner, Lynn Affrica Felicitas, Ettich, Julia, Balles, Helene, Lapp, Dorothee Johanna, Mossner, Sofie, Bassenge, Christin, Ouzin, Meryem, Hanenberg, Helmut, Scheller, Jürgen, Floss, Doreen Manuela |
| المصدر: |
Biological Chemistry; Jul2024, Vol. 405 Issue 7/8, p531-544, 14p |
| مصطلحات موضوعية: |
TRANSMEMBRANE domains, SYNTHETIC receptors, CYTOKINE receptors, DIMERIZATION, LYMPHOCYTIC leukemia, CYSTEINE, SYNTHETIC biology |
| مستخلص: |
Naturally occurring gain-of-function (GOF) mutants have been identified in patients for a variety of cytokine receptors. Although this constitutive activation of cytokine receptors is strongly associated with malignant disorders, ligand-independent receptor activation is also a useful tool in synthetic biology e.g. to improve adoptive cellular therapies with genetically modified T-cells. Balanced Interleukin (IL-)7 signaling via a heterodimer of IL-7 receptor (IL-7Rα) and the common γ-chain (γc) controls T- and B-cell development and expansion, whereas uncontrolled IL-7 signaling can drive acute lymphoid leukemia (ALL) development. The ALL-driver mutation PPCL in the transmembrane domain of IL-7Rα is a mutational insertion of the four amino acids proline-proline-cysteine-leucine and leads to ligand-independent receptor dimerization and constitutive activation. We showed here in the cytokine-dependent pre-B-cell line Ba/F3 that the PPCL-insertion in a synthetic version of the IL-7Rα induced γc-independent STAT5 and ERK phosphorylation and also proliferation of the cells and that booster-stimulation by arteficial ligands additionally generated non-canonical STAT3 phosphorylation via the synthetic IL-7Rα-PPCL-receptors. Transfer of the IL-7Rα transmembrane domain with the PPCL insertion into natural and synthetic cytokine receptor chains of the IL-6, IL-12 and Interferon families also resulted in constitutive receptor signaling. In conclusion, our data suggested that the insertion of the mutated PPCL IL-7Rα transmembrane domain is an universal approach to generate ligand-independent, constitutively active cytokine receptors. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
